The objective of the proposed research is to continue the study of the interactions at the molecular level between known and potential antineoplastic drugs and cellular macromolecules with special emphasis on those drugs which interact with DNA to alter its structure and function. The use of inhibitors continues to be a potent tool for the study and understanding of basic cellular control mechanisms, both normal and abnormal (malignant). It is felt that some of the more subtle differences between normal and neoplastic cells may be elucidated by comparing the effects of known anticancer drugs on these two cell types. The details of the drug-macromolecular interactions will be studied using; (1) Cell-free systems, (2) simple bacterial and bacteriophage systems, (3) established mammalian cell lines and (4) primary cultures derived from human cancers. In this way the knowledge gained using the simpler systems can be accumulated and subsequently extended to the more complex mammalian systems and ultimately to human cancer cells. More knowledge of these drug-macromolecule interactions can only result in the more effective clinical use of the drugs or combinations of drugs as well as providing some basis for the development of new drugs which will better meet the requirements of minimum toxicity to normal cells and maximum effectiveness against malignant cells. We are using a wide variety of techniques including: autoradiography; light and electron microscopy; ultracentrifugation analyses; genetic methodology; chromatographic and electrophoretic techniques; general biochemical methodology and enzyme analyses. Thus we plan to continue our multi-faceted approach using a variety of cell systems and employing cytogenetic, molecular biological, biochemical and biophysical methodology.